The enantioselective hydrogenation of β-ketoesters is an important industrial process for the production of optically active 3-hydroxyesters by means of organic synthesis. The optically active 3-hydroxyesters are important intermediates for producing pharmaceuticals, vitamins or natural products. For example, L-carnitine is produced by amination of ethyl-4-chloro-3-hydroxybutyrate, which can be obtained by hydrogenation of the respective β-ketoester.
Carnitine (vitamin Bt; 3-hydroxy-4-trimethylammonio-butanoate) is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is used as a nutritional supplement. Carnitine exists in two stereoisomers. The biologically active form is L-carnitine, whilst its enantiomer, D-carnitine, is biologically inactive.
When producing L-carnitine in an industrial process, it is desirable to produce the biologically active L-form in high purity.
Various methods have been described in the art for converting β-ketoesters to β-hydroxyesters. In many processes, β-ketoesters are hydrogenated in the presence of an optically active ruthenium catalyst. In these catalysts, a central ruthenium ion is bound in a chelate complex.
For example, WO 2005/049545 discloses methods for preparing enantiomerically pure (S)- or (R)-4-halo-3-hydroxybutyrate in the presence of a ruthenium chelate complex, which comprises a bidentate ligand having two phosphorous binding sites. The chiral ligand is referred to as “Fluoxphos” and comprises four fluorine atoms.
Further catalysts and methods for producing optically active alcohols from β-ketoacid esters are disclosed in EP 0 295 109 A1. The inventors suggest the use of ruthenium catalysts with BINAP and derivatives thereof. In examples 1-17, various substrates are hydrogenated in the presence of such catalysts. However, satisfactory total yields and optical yields of optically active alcohols are only obtainable for some specific reactions.
Other ruthenium-based chiral catalysts for converting β-ketoesters into 3-hydroxyesters are disclosed in EP 0 366 390 A2. In the examples, the hydrogenation of methyl-3-hydroxybutyrate with a large variety of catalysts is studied. However, the total yield and optical yield of the desired product are only sufficient for a limited number of catalysts. For most catalysts, the yields are below 90%, which is not satisfactory for a large-scale industrial production.
Pavlov et al. (Russ. Chem. Bull., 2000, 49, p728-731) studied the efficiency of the enantioselective hydrogenation of β-ketoesters in the presence of BINAP ruthenium complexes. They found that process conditions, such as solvent, pressure and temperature, but also specific combinations of substrate and catalyst have an impact on the total yield and enantiomeric yield. The reactions carried out according to Pavlov et al. require relatively high amounts of catalysts and solvents and high pressure, whereas the yields are often not sufficient.
Thus, processes known in the art often do not provide sufficient yield. However, for an efficient industrial production, it is important to achieve a high total yield as well as a high optical yield. This problem is discussed in WO 03/097569 A1 (para. bridging pages 2 and 3). The inventors conclude that the prior art does not provide methods, which are practical on a commercial scale. Further, the prior art would require low substrate to catalyst ratios to achieve a good enantioselectivity. Since chiral ligands, such as BINAP or other bisarylbiphosphine-based ligand catalysts are expensive, processes requiring low substrate-to-catalyst-ratios are generally uneconomic.
Therefore, the authors suggest a specific continuous process, which should overcome the problems of prior art processes. When converting ethyl-4-chloroacetoacetate into ethyl-4-chloro-3-hydroxybutyrate by the continuous process, relatively high yields and optical yields were obtained whilst using relatively low concentration of catalysts (example 3, figure). However, these advantages are only achieved by carrying out the reaction in a relatively complicated continuous process. The hydrogenation reactor requires high pressure (between 90 and 100 bar) and exact process control In order to maintain the continuous process conditions, dedicated equipment such as high pressure pumps and devices for supplying, removing and separating the components are necessary. Further, such metal catalysts in solution are highly sensitive against “poisoning” by traces of oxygen. Therefore, the catalyst can become inactivated during storage, leakage of the equipment or when components are not degassed sufficiently. As a result, the yield and selectivity are reduced.